Minimal change disease following COVID-19 vaccination: A systematic review

Background The newly developed COVID-19 vaccines are highly effective and safe. However, a small portion of vaccine recipients experience a wide range of adverse events. Recently, glomerular disease, including the development of Minimal Change Disease (MCD), has been observed after administration of different COVID-19 vaccines, although causality remains a matter of debate. Aim The aim of this systematic review was to comprehensively examine the available literature and provide an overview of reported cases of MCD following vaccination against SARS-CoV-2. Results We identified 46 eligible articles which included 94 cases with MCD following COVID-19 vaccination of which one case was reported twice due to a second relapse. Fifty-five participants were males (59.1%, 55/93) and 38 (40.9%, 38/93) were females with a mean age of 45.02 years (SD:20.95). From the included patients 50 (50/94, 53.1%) were described as new-onset and 44 (46.9%, 44/94) as relapse. On average, symptomatology developed 16.68 days (SD: 22.85) after the administration of the vaccine irrespective of the dose. Data about symptoms was reported in 68 cases with the most common being oedema (80.8%, 55/68), followed by weight gain (26.5%, 18/68) and hypertension (16.1%, 11/68). In terms of outcome, more than half of the patients went into remission (61%, 57/94), while 18 recovered or improved post treatment (19.1%, 18/94). Two people relapsed after treatment (2.1%, 2/94) and two cases (2.1%, 2/94) were reported as not recovered. Conclusion MCD is possibly a condition clinicians may see in patients receiving COVID-19 vaccines. Although this adverse event is uncommon, considering the limited published data and the absence of confirmed causality, increased clinical awareness is crucial for the early recognition and optimal management of these patients.


Introduction
In late 2019, a global pandemic, which created extraordinary socio-economic consequences, emerged due to an outbreak of an uncommon viral pneumonia [1][2][3].The aetiological factor was later identified as a previously unknown strain of coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), responsible for the onset of coronavirus dis-

Literature search
Two reviewers (KSK, JDL) searched PubMed and Scopus library databases from inception until January 2023 independently.The search included the following terms: "(COVID 19 vaccin* OR SARS-COV2 vaccin*) AND (minimal change disease OR glomerulonephritis OR nephrotic OR nephritic)".There were no limitations placed regarding study design, geographic region, or language.Additionally, a manual search of references cited in the included articles and relevant published reviews was conducted to identify any missed studies.Discrepancies during the literature search were resolved by a third investigator (DS).

Eligibility criteria
We included studies that provided data for new onset or relapse of MCD following COVID-19 vaccination with at least one dose.All study designs were considered eligible for inclusion.Review articles, abstracts submitted in conferences and non-peer reviewed sources were not eligible for inclusion.Studies on in vitro and animal models were excluded.

Data extraction and handling
In all studies, patient data was retrieved and handled by two authors (JDL, JD) who conducted the data extraction independently.We collected the following information: sex, age, comorbidities, vaccine type, number of doses received, presenting complains and symptoms, history of previous COVID-19 infection, laboratory tests including antibodies, primary diagnosis, imaging findings, therapeutic management and clinical outcome.Any disagreements were discussed and resolved by a third author (KSK).

Quality assessment
The quality of the included studies was assessed using the criteria established by the Task Force for Reporting Adverse Events of the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) [19].The evaluation was based on the satisfactory reporting of 12 different elements, including the title, patient demographics, current health status, medical history, physical examination, patient disposition, drug identification, dosage, administration/drug reaction interface, concomitant therapies, adverse events, and discussion.Each element was assigned a score of either 0 (lack of information) or 1 (information present) for the studies.

Study characteristics
The initial literature search yielded 830 publications.In the first screening 777 studies were excluded as irrelevant.Forty-six studies  were found to be eligible for the systematic review based on the predefined inclusion criteria ( Fig 1).Twenty of the studies were conducted in Asia, 16 in Europe, 9 in Americas, and 1 in Australia.Seven studies were case series and 39 were case reports (Table 1).
We identified a total of 94 cases of MCD following COVID-19 vaccination, of which one case was reported twice after relapsing following the second dose.

Quality of the studies
The mean quality score indicated that the studies reported on average 10 of the recommended 12 elements, defined by the guidelines.Ten studies had a perfect score of 12 while the second most common score was 11 (S2 Table ).

Discussion
The administration of COVID-19 vaccines has not been deemed as a causative factor for kidney disease.However, recent findings, primarily derived from case reports and case series, indicate that various kidney disorders such as Minimal Change Disease (MCD), IgA nephropathy, membranous glomerulopathy, and IgG4-related disease have been observed to initially manifest or relapse subsequent to SARS-CoV-2 vaccination.These observations suggest a potential link between COVID-19 vaccination and the occurrence or recurrence of MCD.In this study, we conducted a thorough screening of the existing literature to present a comprehensive summary of documented cases of MCD following SARS-CoV-2 vaccination.Our systematic review identified 46 relevant reports, involving a total of 93 patients, in which MCD was observed subsequent to the administration of various COVID-19 vaccines.In the majority of cases, symptoms began to emerge following the first vaccine dose, and clinical improvement was reported for most patients.

Results in the context of the literature
MCD consists the most frequent cause of nephrotic syndrome in childhood and rarely affects adults.MCD generally presents with a sudden onset of symptoms and signs of nephrotic syndrome and requires histologic confirmation in adults.Its pathogenesis remains to be elucidated, however, evidence points towards T cell dysfunction being a major mechanism [66].It has been previously proposed that a glomerular permeability factor is produced, attacks the glomerular filtration barrier and leads to the destruction of podocytes and subsequent proteinuria.It's most commonly idiopathic, but infections, medications, vaccinations, malignancies, and allergens are among the secondary etiologic factors [67].Infections including syphilis, hepatitis C and tuberculosis, and vaccinations against hepatitis B, influenza, measles and rubella are established triggering factors for the relapse of primary glomerulonephritis, potentially with a similar mechanism involved in the development of MCD [68].
In animal models the prevalence of CD8+ suppressor T-cells and subsequent cytokineinduced injury has been observed in the active phase of MCD [60,69].This could provide a possible explanation for the aforementioned cases since the existent vaccinations against COVID-19 are known to strongly induce T-cell activation and this could lead to immune mediated podocyte damage.It's worth noting that during the vaccine-induced T-cell activation, interferon gamma and inerleukin-2 (IL-2) are increased and IL-2 has been found to be raised in the acute phase and relapses of idiopathic nephrotic syndrome [22].Direct podocyte injury could also be implicated in MCD in both COVID-19 infection and vaccination and interestingly ACE-2 is expressed in podocytes, however there is currently not adequate evidence to establish a causative mechanism.Moreover, similarities between vaccine adjuvants and human proteins could lead to immune cross-reactivity and drug-induced hypersensitivity reactions through molecular mimicry [70,71].
Even though MCD most commonly presents during childhood, it has been reported mainly in adults following COVID-19 vaccination, however this is to be expected considering the high vaccination rates in these age groups.MCD symptomatology commenced within 3 weeks from the first dose in more than half of the patients, although a significant amount of people developed symptoms after the second dose, which could be associated to the amplitude of the immune response.Symptoms did not differ from those commonly reported in literature and glucocorticoids were chosen as first-line treatment in 91.5% of the cases.Concerns about potential interference of immunosuppressive agents such as rituximab in the vaccination efficacy has been raised, however, relevant treatment to achieve best clinical response should be prioritised over immunisation in these cases.Overall the vast majority responded to treatment and maintained positive outcomes.

Strengths and limitations
Our study represents the first systematic review conducted on the relationship between COVID-19 vaccination and the occurrence or relapse of MCD.Our findings present a comprehensive overview of published reports with quality assessment of the included studies.
However, it is important to highlight certain limitations linked to our study.One major limitation stems from the low quality nature of the case reports and case series included in this review, which can impact the validity and generalizability of the conclusions.These studies are susceptible to potential biases including overinterpretation and selection bias.Consequently, while the reported findings are interesting, they may not necessarily provide an accurate representation of the true effect of COVID-19 vaccination in relation to renal dysfunction.Therefore, establishing causality requires insight from mechanistic studies and well-designed appropriately powered prospective studies.

Conclusion
While the current COVID-19 vaccines are generally considered safe and the advantages of vaccination outweigh the potential occurrence of adverse events, it is possible for patients to develop mild to moderate side effects, including complications related to renal dysfunction.Minimal change disease is possibly a condition clinical doctors and other healthcare professionals may expect to see in patients receiving COVID-19 vaccines.Although this adverse event is uncommon, considering the limited published data and the absence of confirmed causality, increased clinical awareness is crucial for the early recognition and optimal management of these patients.